Obesity is very common in nowadays society. Approximately 25% to 35% of the population of the Western world is overweight. Overweight is associated with considerable morbidity and mortality. Obesity is the second preventable death cause in de US and a major risk factor for coronary heart disease, hypertension and diabetes mellitus type II. A reduction of body weight with 10% has shown to decrease the risk for coronary heart disease with 20%. Besides this, overweight and/or excess body fat is generally considered a problem, influencing social satisfaction and perception of health.
Attempts to combat overweight are often focussed on alteration of the diet or manipulation of the appetite in order to reduce caloric intake. However, there is accumulating evidence that low energy output predisposes individuals to weight gain and obesity, whether the low energy output is caused by low metabolic rate, physical inactivity or both. Increased energy metabolism therefore is an attractive target for treating overweight. Additionally, it allows people to maintain food intake at socially acceptable levels.
A main function of an adipocyte is the storage of triglycerides for later use as an energy source. The triglycerides can be synthesized from glucose and fatty acids present in the diet. Stimulation of the process in which triglycerides in adipose tissue are hydrolyzed into fatty acids (FA) and glycerol (lipolysis), which are subsequently released in the blood stream and oxidized by tissues in the body to yield energy, results in an increased energy metabolism. Such stimulation of lipolysis in order to mobilize excess stored energy in the form of fat is therefore an attractive mechanism to treat obesity and reduce body fat.
In a natural situation the rate of lipolysis is tightly regulated in the mammalian body, to ensure an adequate supply of energy to tissues at all times, e.g. at times of limited as well as of high demand. Enzymes involved in lipolysis are activated and inactivated by phosphorylation. The changes in phosphorylation state are the result of reversible cAMP-dependent protein phosphorylation reactions that occur at a single serine residue. A further factor contributing to lipolysis of triglycerides in adipose tissue is the translocation of the hormone sensitive lipase (HSL) from the cytosol to the fat droplets. HSL is translocated to the surfaces of the fat droplets as a direct consequence of activation of HSL by phosphorylation. HSL phosphorylation occurs in response to binding of a hormone to a receptor and subsequent activation of cAMP-dependent protein kinase A cascades.
The main endogenous lipolytic agents are the catecholamines, which bind to the adrenergic receptors of adipocytes, thereby initiating the cAMP-dependent cascades in the cell causing increased lipolysis.
Pharmacological interventions with lipolysis stimulating agents (e.g. ephedrine) have been shown to induce bodyweight reduction. Ephedrine is both an indirect sympathomimetic causing release of catecholamines (norepinephrine) from sympathetic nerve endings and a direct agonist of beta-adrenergic receptors [Astrup, 1992]. As a consequence, lipolysis is stimulated.
Furthermore, the ingestion of alpha2-adrenoreceptor antagonists, like yohimbine, have been shown to induce lipolytic activity [Galitzki, 1991]. As a consequence of the stimulated lipolytic activity, the blood plasma levels of non-esterfied fatty acids can increase with more than 100%.
However, several side effects are associated with the use of lipolysis stimulating components for the reduction of body weight. Many of these problems have been disregarded until now.
One of the side effects of the use of components capable of stimulating lipolysis is a reduced insulin sensitivity. Reduced insulin sensitivity often leads to the disease diabetes, especially diabetes type II. As a consequence of reduced sensitivity, the human body starts to increase the secretion of insulin into the bloodstream, leading to enhanced levels of insulin in the blood plasma. Higher serum insulin levels are significantly associated with the development of metabolic manifestations like obesity.